Normal human airway epithelia absorb Na+ and secrete Cl- to maintain the volume and composition of the periciliary liquid layer. The coordinated regulation of these opposing ion transport processes is important for efficient airway mucociliary clearance because severe chronic airway infections develop in cystic fibrosis (CF) patients, whose airways exhibit raised and abnormally regulated Na+ absorption and lack cAMP-dependent Cl- secretion. Moreover, strategies to normalize these functions in CF airways appear to be therapeutic. The mechanisms by which normal airway epithelia routinely coordinate Na+ absorption and Cl- secretion, if known, might provide new insight into the genesis and therapy of other airways diseases. New information to investigate this gap in our understanding is available. Purinergic receptors that recognize ATP and UTP (P2U-R) are present on the airway surface. Thus, nucleotide release and metabolism in the airway surface liquid compartment will regulate the activity of this receptor, and the activity of functions that it controls. Airway epithelial apical membrane channels that mediate epithelial Na+ absorption (ENaC) and cAMP-dependent Cl- secretion (CFTR) have been cloned. We propose to probe critical molecular details of the functions and regulatory interactions of these elements, expressed in native epithelia and in heterologous cells, by combining electrophysiological techniques and nucleotide biochemistry. We hypothesize that the endogenous extracellular nucleotides in airway surface liquid will be an important physiologic and pathophysiologic regulator of airway surface liquid metabolism. Finally, we speculate that interactions between CFTR and ENaC cause the regulation of Na+ absorption in airway epithelium to differ markedly from regulation of Na+ absorption in salt conserving epithelia. Better understanding of the function and regulation of these components of mucociliary transport will enhance the ability to develop effective pharmacotherapies for lung diseases.